Monocyte chemoattractant protein-1 (MCP-1), a pivotal chemokine mediating the infiltration and activation of monocyte/macrophages in the brain is consistently observed in HIV and SIV CNS disease. Recently, a dinucleotide polymorphism in the human MCP-1 promoter was linked to increased susceptibility to HAD, strengthening the role of MCP-1 in HIV neuropathogenesis. Intriguingly, these polymorphisms result in increased expression of MCP-1 but decreased binding of transcriptional activators. Since the mechanisms regulating MCP-1 expression in the CNS of HIV-infected individuals are not known, it is difficult to understand how these and potentially other genetic variations in the MCP-1 promoter influence MCP-1 expression in vivo. The goal of this application is to elucidate the mechanisms that regulate MCP-1 transcription in the CNS. These mechanisms are important for the design of immunomodulatory therapeutics to supplement antiviral drugs, particularly in the CNS where antiviral drugs are least effective. Using an accelerated consistent SIV macaque model, we have demonstrated that activation of ERK/MAPK correlates with transient expression of MCP-1 during acute infection. Sustained activation of p38/MAPK correlates with escalating ratios of CSF:plasma MCP-1 that correlate with severity of CNS lesions. Further, treatment of SIV-infected macaques with minocycline, a potent neuroprotective, anti-inflammatory drug significantly reduced activation of p38, reduced ratios of CSF:plasma MCP-1 and reduced severity of CNS lesions. These results suggest a mechanistic link between p38 activation and MCP-1 expression. Sustained activation of p38/MAPK results in nucleosomal remodeling, via phosphoacetylation of histone H3, that enhances the accessibility of cryptic, high-affinity binding sites for NF-kappa B in the MCP-1 promoter. We hypothesize that distinct sites in the MCP-1 promoter regulate early vs. late expression of MCP-1 during SIV infection of the CNS and that p38-mediated phosphoacetylation of histone H3 is integral to the mechanism regulating late MCP-1 transcription in vivo. Aim 1 will identify specific binding sites and transcription factors regulating MCP-1 transcription in macaque (longitudinally) and human brain (end stage disease) and determine if histone H3 phosphoacetylation is involved in chromatin remodeling of the MCP-1 promoter in vivo. Aim 2 will determine if decreased phosphoacetylation of histone H3 at the MCP-1 promoter correlates with the decreased activation of p38 and decreased expression of MCP-1 mRNA observed in SIV-infected macaques treated with minocycline. Aim 3 will determine if and how genetic variations in the macaque and human MCP-1 promoter impact binding of regulatory factors to the MCP-1 promoter in the CNS.